Alcobra Corporate Presentation November 2014 NASDAQ: ADHD MDX is an investigational new drug and is not available for commercial distribution 1 Forward-Looking Statements This presentation includes statements that are, or may be deemed, ‘‘forward-looking statements.’’ In some cases, these forward-looking statements can be identified by the use of forward-looking terminology, including the terms “believes,” “estimates,” “anticipates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “will,” “should,” “approximately,” potential” or, in each case, their negative or other variations thereon or comparable terminology, although not all forward-looking statements contain these words. They appear in a number of places throughout this presentation and include statements regarding our intentions, beliefs, projections, outlook, analyses or current expectations concerning, among other things, the expected milestones of the development of the various indications and next steps with respect thereto, including meeting such milestones (if met) successfully and at the time indicated in this presentation, the potential of MDX to address the market opportunity in ADHD and the potential to use MDX to treat Fragile X Syndrome. In addition, historic results of scientific research and clinical and preclinical trials do not guarantee that the conclusions of future research or trials would not suggest different conclusions or that historic results referred to in this press release would not be interpreted differently in light of additional research and clinical and preclinical trials results. By their nature, forward-looking statements involve risks and uncertainties because they relate to events, competitive dynamics, and healthcare, regulatory and scientific developments and depend on the economic circumstances that may or may not occur in the future or may occur on longer or shorter timelines than anticipated. Although we believe that we have a reasonable basis for each forward-looking statement contained in this presentation, we caution you that forward-looking statements are not guarantees of future performance and that our actual results of operations, financial condition and liquidity, and the development of the industry in which we operate may differ materially from the forward-looking statements contained in this presentation as a result of, among other factors, the factors referenced in the “Risk Factors” section of the annual report on Forma 20-F for the year ended December 31, 2013 filed with the Securities and Exchange Commission on March 28, 2014. In addition, even if our results of operations, financial condition and liquidity, and the development of the industry in which we operate are consistent with the forward-looking statements contained in this presentation, they may not be predictive of results or developments in future periods. Any forward-looking statement that we make in this presentation speaks only as of the date of such statement, and we undertake no obligation to update such statements to reflect events or circumstances after the date of this presentation. MDX is an investigational new drug and is not available for commercial distribution 2 Alcobra’s Value Proposition • MDX is a proprietary extended-release oral formulation of metadoxine Metadoxine Extended Release (MDX) (pyridoxol L-2-pyrrolidone-5-carboxylate) • MDX has shown pro-cognitive benefits in attention, executive function, learning and memory in multiple clinical and pre-clinical studies • MDX was well-tolerated in clinical studies, had no effect on CV measures, and has shown no potential for abuse or addiction Attention deficithyperactivity disorder (ADHD) Fragile X Syndrome • Unlike most drugs available in the $8.3bn US ADHD market, MDX is a not a stimulant and has a differentiated MoA • Showed efficacy signal in multiple, placebo-controlled ADHD trials • Analysis of secondary endpoints and sub-scales suggest impact on attention and executive function • Fragile X Syndrome is a rare neuro-genetic disorder associated with Autism • Company obtained Orphan Drug Designation from FDA in December 2013 • MDX showed significant improvements in working memory, learning and social interaction in pre-clinical Fragile X mouse studies MDX is an investigational new drug and is not available for commercial distribution 3 About Metadoxine Extended Release (MDX) MDX • MDX contains Pyridoxine Pyroglutamate (Metadoxine) • MDX is a once-daily, proprietary dual-release formulation of Metadoxine Metadoxine Experience • Since the 1980s, Metadoxine has been available in immediate release forms for acute treatment of Alcohol Intoxication and chronic treatment of Alcoholic Liver Disease in Italy, Portugal, Hungary, Russia, India, China, Mexico and Thailand • An estimate of 13+ million patient days of therapy on Metadoxine have been administered since its introduction; To our knowledge, in 30+ years of product availability, no major safety/tolerability issues have been published • Multiple peer reviewed papers have been published on the use of Metadoxine at ~1500mg levels(1) 1. Caballeria et al (J Hep, 1998) – n=69, 3 months, 1500mg Cacciatore et al (Clin Trial J, 1988) – n=30, 300mg IM twice daily for 30 days, then 500mg tablet 3 times a day for 5 months (6 months – 1500mg) Bono et al (Int J Clin Pharm Res, 1991) – n=20, 900mg IV twice daily (10 days - 1800mg) MDX is an investigational new drug and is not available for commercial distribution 4 Intellectual Property Over 30 submitted patents globally may provide multiple layers of protection to 2028 and beyond: • Protection of Extended Release/Slow Release formulations of Metadoxine – US PATENT #8,476,304 ISSUED JULY 2013 • Protection of use of Metadoxine for cognitive disorders and impairments – US PATENT #8,710,067 ISSUED APRIL 2014 • Protection of new Metadoxine derivatives – US PATENT #8,889,715 ISSUED NOVEMBER 2014 • Protection of combination therapies containing Metadoxine • Protection of Metadoxine manufacturing process MDX is an investigational new drug and is not available for commercial distribution 5 Metadoxine Mechanism of Action Metadoxine is a monoamine-independent GABA transmission modulator • Monoamine-independent MOA • Metadoxine is a 5-HT2B receptor antagonist • Metadoxine shows no effect on dopamine, norepinephrine, or serotonin levels in vivo • Metadoxine shows no binding to dopamine, norepinephrine, or serotonin transporters in vitro • GABA transmission modulator • Metadoxine binds the GABA transporter • Metadoxine displays a dose-dependent, reversible enhancement of GABAergic inhibitory transmission via presynaptic modulations in striatal medium spiny neurons Rubin J, et al, US Psychiatric & Mental Health Congress; September 20–23 , 2014; Orlando, FL. MDX is an investigational new drug and is not available for commercial distribution 6 Metadoxine PhMRI Pre-Clinical Study • Metadoxine mainly affects the Prefrontal Cortex, thalamus, striatum, primary somatosensory cortex, and the cerebellum Placebo Metadoxine • These regions are involved in executive function, learning and memory, motivation, information integration and processing, attention and cognition • Metadoxine does not affect the mesolimbic dopaminergic regions, including the nucleus accumbens, which are areas associated with abuse potential • Multiple pre-clinical findings additionally demonstrate that metadoxine is likely to be devoid of recreational abuse potential in humans MDX is an investigational new drug and is not available for commercial distribution 7 ADHD Market Attention deficit-hyperactivity disorder (ADHD) is a neurobehavioral disorder characterized by difficulty in maintaining attention, and in some cases, hyperactivity and impulsive behavior. 70 US ADHD Market TRxs (millions) TRxs (millions) 60 50 40 30 20 40.0 43.7 2008 2009 49.1 54.2 56.7 60.2 2011 2012 2013 10 0 2010 2013 Total ADHD Sales = $8.3 billion ADHD affects 8-10% of school-aged children and 4-5% of the adult population Source: IMS, NPA, TRxs MDX is an investigational new drug and is not available for commercial distribution 8 Marketed ADHD Treatments Ritalin, Concerta, Adderall, Vyvanse Strattera, Intuniv, Kapvay Psychostimulants Non-stimulants Strong Effect Non-Scheduled Rapid Onset Scheduled Substance Significant Side Effects Titration required Moderate Effect Delayed onset Significant Side Effects Titration required MDX is an investigational new drug and is not available for commercial distribution 9 ADHD Medications have shown Rapid Market Uptake and Revenue Growth Product (launch) Class Owner Years to Peak Share Peak Share Peak Sales Concerta (2000) Stimulant J&J 2 26% $1.3 BB Adderall XR (2001) Stimulant Shire 5 26% $1.1 BB Strattera (2002) Non-Stimulant Eli Lilly 2 18% $667 MM Focalin XR (2005) Stimulant Novartis 3 6% ~$400 MM Vyvanse (2007) Stimulant Shire ($2.6bn acquisition) 6 17% $1.2 BB* Intuniv (2009) Non-Stimulant Shire 4 4% $335 MM MDX is an investigational new drug and is not available for commercial distribution 10 ADHD Clinical Studies with MDX Phase of Study Study Identifier Number of Subjects & Sites Study Assessments Study Design & Type of Control Duration of Treatment Results Phase I AL0098 NCT01933997 16 healthy adult subjects 1 site Safety, tolerability and PK Single center, open-label, repeated-dose study 5 days Bioavailability parameters met the U.S. FDA criteria. Favorable safety profile. Phase IIa AL0064,5 NCT00995085 40 adult subjects 1 site Efficacy, safety and tolerability Open-label, single-dose, single center study. Single dose Endpoints reached with statistical significance. Favorable safety profile. Phase IIb AL0081,2,3,4,5 NCT01243242 120 adult subjects 2 sites Efficacy, safety and tolerability Randomized, double-blind, placebo-controlled, parallelgroup, multicenter study. 6 weeks Endpoints reached with statistical significance. Favorable safety profile. Phase IIb AL0114,5,6 NCT01685281 36 adult subjects 1 site Efficacy, safety and tolerability of two doses Randomized, double-blind, placebo-controlled, crossover-comparison, singlecenter study. Single dose Rapid onset of efficacy on objective performance test; Favorable tolerability profile. Phase III AL0125,7,8 NCT02059642 300 adult subjects 20 sites Efficacy, safety and tolerability Randomized, multicenter, double-blind, parallel, fixeddose Study 6 weeks Primary efficacy endpoint did not reach statistical significance. Trend observed. Other secondary measures showed strong or statistically significant trends. Favorable safety profile. Phase II AL015 NCT02189772 82 adolescent subjects 6 sites Safety, tolerability and PK Randomized, double-blind, multi-center, fixed dose, single administration study Single dose Study ongoing. 1. Manor I, et al. J Clin Psychiatry. 2012;73:1517-1523. 2. Manor I, et al. Postgrad Med. 2013;125:181-190. 3. Manor I et al. Postgrad Med 2013; 125(4): 181190. 4. Adler L. Symposium presentation at the 60th Annual Meeting of the American Academy of Child & Adolescent Psychiatry; October 19–27, 2013; Orlando, FL. 5. Adler L. Symposium presentation at the 61st Annual Meeting of the American Academy of Child & Adolescent Psychiatry; October 20–25, 2014; San Diego, Ca 6. Manor I et al. Postgrad Med 2014; 126(5): 7-16. 7. Posters presented at AACAP’s 61st Annual Meeting, San Diego, CA, October 23, 2014 8. Data on file MDX is an investigational new drug and is not available for commercial distribution 11 MDX Safety & Tolerability Treatment with MDX once daily in multiple trials has been well tolerated The number of patients reporting AEs has been similar between the MDX and placebo treatment groups The most common AEs reported have been headache (15.1% in the MDX group vs 12.3% in the placebo group), nausea (8.6% vs 6.2%), and fatigue (7.2% vs 8.2%)1 No drug-related serious AEs have been reported No clinically significant abnormalities in laboratory values, vital sign measurements, ECG parameters, C-SSRS, or findings during clinical examination, including neurological examination, have been observed 1. Data based on AL012, largest trial to date. MDX is an investigational new drug and is not available for commercial distribution 12 MDX Trials: Efficacy and Variability in Context LS Mean ± SD MDX Studies Phase III MDX Study; N=300 Week 0 1 −12.0 ± 12.6 MDX 2 3 Phase IIb MDX Study1; N=120 −12.5 ± 8.8 MDX −8.9 ± 9.2 Placebo Atomoxetine Studies Mean ± SD Michelson D et al, 20032 Study 1 N = 267 Atomoxetine −9.5 ± 10.1 Placebo −6.0 ± 9.3 Study 2 N = 248 Atomoxetine Placebo CAARS change from baseline −9.9 ± 11.4 Placebo 4 5 6 Placebo MDX -5.9 -6.5 -8.5 -8.7 -9.4 -10.1 -9.9 -12 -12 -11 −10.5 ± 10.9 −6.7 ± 9.3 Phase III study affected by high placebo response and variability 1. Manor I, et al. J Clin Psychiatry. 2012;73:1517-1523. 2. Michelson D, et al. Biol Psychiatry. 2003;52:112-120. MDX is an investigational new drug and is not available for commercial distribution 13 Summary of MDX ADHD Clinical Studies Overall findings to date: Efficacy signal in multiple, placebo-controlled trials Analysis of secondary endpoints and sub-scales suggest impact on attention and executive function Rapid response, within first day, as demonstrated on objective performance tests Favorable tolerability Absence of cardiovascular effects No potential for abuse or addiction seen Fixed dose (no need for dose titration) MDX is an investigational new drug and is not available for commercial distribution 14 Next Steps in MDX ADHD Development Complete analysis of Phase III Adult study in 4Q 2014 Complete patient enrollment in Phase IIb pediatric study in 4Q 2014 Post FDA meeting, Company plans to initiate Phase III studies in adults and pediatric More rigorous patient selection to address suggestibility and severity of patients Enhanced real-time monitoring Evaluate structural elements of study design (e.g., placebo lead-in1, Sequential parallel comparison design2) 1 2 Michelson D, et al. Biol Psychiatry. 2003;52:112-120. Fava M, et al. Psychother Psychosom. 2003;72:115-127. MDX is an investigational new drug and is not available for commercial distribution 15 MDX – Potential Use in Fragile X A rare neuro-genetic disorder caused by loss of FMR1 protein Most common known genetic cause of autism Most common inherited form of intellectual disability Unmet need: No FDA approved therapies Rationale for MDX study: Fragile X is associated with GABA transmission imbalance1 Pro-cognitive properties of MDX observed in other trials Pre-clinical animal model 1 Berry-Kravis EM et al. Sci Transl Med 2012; 152(4): 1-7 MDX is an investigational new drug and is not available for commercial distribution 16 Fragile X Market Assumptions by Age Group Adult Pediatric 1/4,000 males 1/8,000 females Prevalence1 Diagnosed Patients 2 95% FXS Patients with Attention Problems 3 Patients Treated for Attention Problems 4 85% 80% ~35% ~50% 1 FXS prevalence NIH, April 2012: http://ghr.nlm.nih.gov/condition/fragile-x-syndrome 2 Bailey DB et al. (2009). No change in the age of diagnosis for fragile x syndrome: findings from a national parent survey 3 Estimated from caregiver surveys (Bailey, AJMG, 2008) 4 Estimated from caregiver surveys (Bailey, 2008 & 2012; Berry-Kravis, 2012). MDX is an investigational new drug and is not available for commercial distribution 17 Pre-Clinical Studies of MDX in Fragile X In a well-validated animal model for Fragile X, Metadoxine showed in two separate studies: Significant improvements in working memory, learning and social interaction Significant changes in brain & blood biomarkers including pAkt and pERK Fear conditioning task Social interaction NS NS p<.0001 p<.0001 40 ns Sniffing duration (Sec) Freezing (% of 5 min) 25 p<.0001 30 20 10 0 p<.0001 ns 20 15 10 5 0 Wild typePlacebo FX KO-Placebo Wild typeMetadoxine FX KOMetadoxine Wild typePlacebo FX KO-Placebo Wild typeMetadoxine MDX is an investigational new drug and is not available for commercial distribution FX KOMetadoxine 18 MDX Ongoing Phase IIb Clinical Trial in Fragile X (AL014) Phase 2, 6-week, randomized, multicenter, placebo-controlled, double-blind, parallel group, dose-ranging study of MDX once daily in adults and adolescents with FXS 60 adults and adolescents (Age 15-55), 13 study sites (12 in US) Primary endpoint: Inattentive subscale of ADHD RS-IV Secondary endpoints include several efficacy and safety measures Screening Treatment Period Follow-up Period (Double-blind, Placebo-controlled, 1:1) Period V3 D7 V4 D14 V5 D21 2 Weeks V6 D28 V7 D35 MDX low dose once daily for 2 weeks, then increase to high dose once daily as tolerated during Weeks 3 and 4; maintain dose during Weeks 5 and 6 Matching placebo V8 D42 V9 D56 Follow-up V2 Day 0 Randomization Screening V1 Day −14 6 Weeks Study Termination 2 Weeks MDX is an investigational new drug and is not available for commercial distribution 19 MDX Potential in Fragile X – Next Steps Company enrolling patients in a Phase IIb study in adolescents and adults with Fragile X Syndrome Post completion of enrollment and meeting with the FDA, Company to launch Phase III study in Fragile X by YE 2015 Company obtained Orphan Drug Designation in December 2013 Unique formulation/dosing possible MDX is an investigational new drug and is not available for commercial distribution 20 Financial highlights Financial metric As of June 30th 2014 Cash, Cash Equivalents, and ST investments $38.9 million Average quarterly operating expenses YTD (exc. non-cash)1 $6.7 million Average quarterly cash outflows YTD1 $5.6 million Debt $0 Shares outstanding 13.7 million 1 Future expenses and cash outflows may significantly differ from past figures presented above. Future expenses will be a function of the clinical development plan and regulatory pathway MDX is an investigational new drug and is not available for commercial distribution 21 Summary MDX has demonstrated a pro-cognitive effect in multiple clinical and pre-clinical studies and was well tolerated Company holds three issued patents in the US on the extendedrelease PK profile of MDX, the use of MDX to treat cognitive disorders, and new MDX derivatives Upon approval, MDX will address a significant patient need in the ADHD market A rapidly effective non-abusable, non-addictive drug candidate with a differentiated mechanism of action and favorable tolerability Findings suggest an opportunity for MDX in Fragile X Syndrome, a rare neuro-genetic disease and the most common inherited form of autism Multiple data readouts from advanced clinical studies in pediatric and adult ADHD and Fragile X Syndrome expected in 2015 MDX is an investigational new drug and is not available for commercial distribution 22 Alcobra Ltd. NASDAQ:ADHD http://www.alcobra-pharma.com/ MDX is an investigational new drug and is not available for commercial distribution 23
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